RESUMEN
BACKGROUND: Cyclin-dependent kinase 5 (Cdk5) is essential for brain development and function, and its deregulated expression is implicated in some of neurodegenerative diseases. We reported earlier that the forebrain-specific Cdk5 conditional knockout (cKO) mice displayed an early lethality associated with neuroinflammation, increased expression of the neuronal tissue-type plasminogen activator (tPA), and neuronal migration defects. METHODS: In order to suppress neuroinflammation in the cKO mice, we first treated these mice with pioglitazone, a PPARγ agonist, and analyzed its effects on neuronal loss and longevity. In a second approach, to delineate the precise role of tPA in neuroinflammation in these mice, we generated Cdk5 cKO; tPA double knockout (dKO) mice. RESULTS: We found that pioglitazone treatment significantly reduced astrogliosis, microgliosis, neuronal loss and behavioral deficit in Cdk5 cKO mice. Interestingly, the dKO mice displayed a partial reversal in astrogliosis, but they still died at early age, suggesting that the increased expression of tPA in the cKO mice does not contribute significantly to the pathological process leading to neuroinflammation, neuronal loss and early lethality. CONCLUSION: The suppression of neuroinflammation in Cdk5 cKO mice ameliorates gliosis and neuronal loss, thus suggesting the potential beneficial effects of the PPARγ agonist pioglitazone for the treatment for neurodegenerative diseases.
Asunto(s)
Quinasa 5 Dependiente de la Ciclina/deficiencia , Encefalitis/tratamiento farmacológico , Encefalitis/mortalidad , Encefalitis/patología , PPAR gamma/agonistas , Prosencéfalo/efectos de los fármacos , Tiazolidinedionas , Animales , Apoptosis/efectos de los fármacos , Quinasa 5 Dependiente de la Ciclina/genética , Quinasa 5 Dependiente de la Ciclina/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalitis/genética , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Gliosis/etiología , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Inmunoprecipitación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/patología , PPAR gamma/metabolismo , Fosfotransferasas/genética , Fosfotransferasas/metabolismo , Pioglitazona , Prosencéfalo/metabolismo , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéuticoRESUMEN
PURPOSE: We performed antegrade thoracic endovascular aneurysm repair via the ascending aorta in selected high-risk patients scheduled for open surgery, in whom an iliofemoral or abdominal aortic approach was not feasible. We present our initial experience with this approach. METHODS: Of 16 consecutive patients who underwent antegrade endovascular aneurysm repair via the ascending aorta at our institution, 3 had an emergency intervention for rupture and 3 had an urgent intervention for impending rupture or complicated aortic dissection. The procedure was scheduled in 10 patients. The median patient age was 77 years. In 13 patients, one or more concomitant procedures were performed. In 6 patients, vascular access for endovascular aneurysm repair was obtained via a branch of the replacement graft. In 10 patients, direct cannulation of the ascending aorta was carried out using 2 pursestring sutures. RESULTS: The initial success rate was 100%. Early mortality occurred in 2 (12.5%) patients because of multiple organ failure in one and heart failure in the other. No patient required a second intervention during follow-up. The mean duration of follow-up was 19 months. CONCLUSION: The antegrade approach is a useful alternative in patients with no access suitable for endovascular aneurysm repair and who are not appropriate candidates for open conventional thoracic aortic surgery. This approach is applicable to selected patients.